Prostate cancer (CaP) is the second leading cause of cancer-related mortality in the United States. There were approximately 27,360 deaths caused by CaP in 2009 [Jemal et al., CA: A Cancer Journal for Clinicians, 59(4): 225-249 (2009)]. Patients who recur after primary ablative therapy respond transiently to androgen deprivation therapy but subsequently progress to hormone-refractory disease for which curative systemic therapies are lacking [Pronzato et al., Annals of Oncology, 16 (Suppl. 4) iv: 80-84 (2005)]. Recent studies have demonstrated that overall survival (OS) of patients with hormone refractory CaP can be modestly extended by vaccination with autologous dendritic cells (DC) loaded with recombinant proteins consisting of granulocyte macrophage colony stimulating factor and prostatic acid phosphatase [Kantoff et al., Genitourinary Cancers Symposium, American Society of Clinical Oncology, Abstract #8 (2010)]. It is widely assumed that improved outcomes might be achieved by vaccinating patients at earlier points in the development of their disease at a time when host immune effector mechanisms remain robust.
The FDA's approval of Sipuleucel-T for the treatment of advanced prostate cancer was a landmark event. The studies leading to the approval of Sipuleucel as well as suggestive results from other prostate cancer vaccine protocols, notably Prostvac® and GVAX, indicates that the clinical course of prostate cancer can be favorably altered by immunotherapeutic manipulation.
Angiogenesis is a complex multistep process involving degradation of the extracellular matrix, endothelial cell (EC) migration, proliferation, and re-differentiation into patent vessels [Folkman and Shing, J Bio Chem. 1992, 267, 10931-10934; Saaristo et al., Oncogene. 2000 Dec. 11; 19 (53):6122-9]. Angiogenesis is normally observed only transiently under physiological conditions such as embryogenesis, wound healing and reproductive functions in adults. Under pathological conditions such as cancer, abnormal angiogenesis supports the survival and progression of human tumors. Tumor angiogenesis is characterized by abnormal vasculature, and hence the targeted disruption of tumor vasculature is an area of growing interest in cancer biology and therapeutics.
Tumor vasculature express distinct proteins, also called angiogenesis-associated proteins, such as, the prostate-specific membrane antigen, extradomain-B fibronectin, and tumor endothelial marker (TEM) [Chang et al., Clin Cancer Res 1999; 5:2674-2681; Khan et al., Angiogenesis 2005; 8(3):183-96; St Croix et al., Science. 2000 Aug. 18; 289(5482):1197-202]. TEM8 is a type-I transmembrane cell-surface protein that is found on tumor blood vessels but not normal adult vasculature or somatic tissues [Hotchkiss et al., Exp Cell Res 2005; 305:133-144; Qin et al., Immunity. 2000 June; 12(6):677-86]. International Publication No. WO 2008/00734 published Jan. 3, 2008 and International Publication No. WO 2008/126413 published Oct. 23, 2008 also relate to TEM8. TEM8 was initially identified in St. Croix et al., as a gene that is predominantly expressed in tumor endothelium [Science. 2000, 289(5482):1197-1202]. However, recent evidence indicates that TEM8 also is expressed on certain tumor cells, tumor associated macrophages and some dendritic cells that have been cultured in vitro with specific cytokine cocktails [Hofineister et al., Cancer Immunol Immunother. 2006 May; 55(5):481-94. Epub 2005 Oct. 12; Kammertoens et al., Trends Mol. Med. 2005 May; 11(5):225-31; Riboldi et al., J Immunol 2005, 175:2788-2792]. Interestingly, the TEM8 gene has been shown to encode the anthrax toxin receptor and shares a high degree of amino acid identity with CMG2 protein in the extracellular integrin-like I domain as well as a conserved metal ion dependent adhesion site motif. TEM8 and CMG2 type-I transmembrane proteins belong to a larger family of the von Willebrand factor type-A domain [Chen et al., J Biol. Chem. 2007 Mar. 30; 282(13):9834-45. Epub 2007 Jan 24].
The immunogenic potential of human TEM8 DNA has been recently reported in a B16F10 murine model [Ruan Z et al, J Immunother 2009; 32:486-491], but TEM8 specific CD8+ CTL responses have apparently not been reported in patients with prostate cancer (CaP). The TEM8 gene was stated to be up regulated in an androgen independent human LNCaP variant line [Singh A P et al, Cancer Lett 2008; 259:28-38]. TEM8 protein was reported to be over expressed in PC-3-Bcl-2 positive CaP tissue xenografts along with other key pro-angiogenic and lympho-angiogenic factors [Sakai et al, Prostate 2009; 69:459-470]. TEM8 expression has also been associated with both nodal involvement and disease progression in colon cancer [Rmali et al., World J. Gastroenterol. 2005 Mar. 7; 11(9):1283-6]. Similarly, elevated levels of TEM8 have been correlated with shorter survival in breast cancer patients [Davies et al., Int J. Oncol. 2006 November; 29(5):1311-7].
Various laboratories have utilized peptide-based cancer vaccines that target tumor-associated antigens (TAA) for active immunotherapy of various tumors [Carbone et al., J Clin Oncol 2005 Aug. 1; 23(22):5099-107. Epub 2005 Jun. 27; Markovic et al., Am J Clin Oncol. 2006 August; 29(4):352-6016; Mittendorf et al., Cancer. 2006 Jun. 1; 106(11):2309-1717; Perambakam et al., Cancer Immunol Immunother. 2006 September; 55(9):1033-42. Epub 2005 Nov. 10]. Recently, there has been growing interest in the potential of anti-angiogenic T cell-based immunotherapy [Hofineister et al., supra; Ishizaki et al., Clin Cancer Res 2006; 12(19):5841-5849; Kammertoens et al., Trends Mol. Med. 2005 May; 11(5):225-31]. Tumor vasculature or tumor stroma serve as a target for immune intervention as endothelial cells (EC) are genetically stable and are not prone to mutations or loss of MHC antigen expression and therefore, are less likely to demonstrate immune escape, compared to tumor cells [Hofineister et al., Cancer Immunol Immunother. 2006, 55(5):481-494. Epub 2005 Oct. 12]. Further, EC are more accessible to the bloodstream than tumor cells which are often encapsulated or blocked off by anatomical barriers and hence, are more efficiently reached by cytotoxic lymphocytes.
Cytotoxic T lymphocytes (CTL) recognize processed peptide antigens presented in association with class I MHC molecules [Townsend and Bodmer, Ann Rev Immunol 7:601-624, 1989]. The ability of a peptide to elicit specific CTL is contingent on its ability to bind to appropriately restricted class I MHC molecule. Allele-specific peptide sequence motifs have been identified for various class I MHC molecules, including, HLA-0201 allele, the most common class I MHC allele in the U.S. population. Previous work identified a 9-mer HLA-A0201 restricted peptide epitope of prostate-specific antigen that elicited specific CTL responses in vitro from normal individuals and patients with prostate cancer [Perambakam et al., Cancer Immunol Immunother. 2002 July; 51(5):263-70; Xue et al., Prostate 1997; 30:73-78]. See also, U.S. Patent Publication No. 2008/0095790 published Apr. 24, 2008.
There, however, remains a need in the art for additional compositions/vaccines for the treatment of prostate cancer and a need in the art for compositions/vaccines for the treatment other cancers.